CN107787325B - 新型肽及其应用 - Google Patents
新型肽及其应用 Download PDFInfo
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- CN107787325B CN107787325B CN201680037340.9A CN201680037340A CN107787325B CN 107787325 B CN107787325 B CN 107787325B CN 201680037340 A CN201680037340 A CN 201680037340A CN 107787325 B CN107787325 B CN 107787325B
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Abstract
本发明涉及由SEQ ID NO:1的氨基酸序列组成的肽或其药学上可接受的盐及其应用。根据本发明,能够有效预防或治疗癌症。
Description
技术领域
本发明涉及一种新型肽,更具体地,涉及一种新型肽及其应用。
背景技术
癌症(或肿瘤)是由活体组织中不可控的细胞增殖引起。癌细胞侵袭周围组织或扩散到其他器官,常常导致死亡。
治疗此类癌症的方法包括手术、放射疗法、化学疗法、免疫疗法等,表现出抗癌效果的肽也正在研究中(国际专利申请公开WO 2007/133033 A1号)。
引文列表
专利文献
(专利文献1)国际专利申请公开WO 2007/133033 A1号,2007年11月22日,摘要
发明内容
由此,本发明是考虑到现有技术中出现的上述问题而做出的,本发明旨在提供一种新型肽。
另外,本发明旨在提供该肽的新用途。
以上未提及的附加技术问题本领域技术人员根据以下描述容易理解。
本发明提供由SEQ ID NO:1的氨基酸序列组成的氨基酸序列(QLHLD)的肽,或其药学上可接受的盐。
上述氨基酸序列中,Q表示谷氨酰胺(Gln),L表示亮氨酸(Leu),H表示组氨酸(His),D表示天冬氨酸(Asp)。
构成上述肽的氨基酸包括L-、D-和DL-形式,所有这些均被引入到本发明中。此外,显而易见的是,Asp可以被解释为具有包括天冬氨酸(aspartic acid)以及天冬氨酸盐(aspartate)作为氨基酸的含义。
所述肽包括其变体,所述变体中本发明的肽结构的一部分通过天然突变或人工突变改变,而不改变其主要活性。
上述药学上可接受的盐的实例可以包括盐酸盐、硫酸盐、磷酸盐、乙酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、乳酸盐、马来酸盐、富马酸盐、草酸盐、甲磺酸盐和对甲苯磺酸盐。
此外,本发明提供了本发明的肽或其药学上可接受的盐的医疗应用,优选用于抗癌应用,更优选用于预防或治疗癌症。在此,术语“治疗”概括地指减少或减轻与癌症有关的症状,术语“预防”用作概括意义,包括从疾病发作前的无症状阶段抑制疾病进展。
癌症可以为转移性癌症。
在本发明中,通过抑制选自癌细胞的侵袭和转移中的至少一种,可以表现出抗癌效果。
因此,本发明提供了包含本发明的肽或其药学上可接受的盐的用于抗癌的组合物。此外,本发明提供了用于治疗或预防癌症的组合物,所述组合物包含本发明的肽或其药学上可接受的盐。癌症的治疗或预防可以通过抑制选自癌细胞的侵袭和转移中的至少一种来实现。该组合物可以为药物组合物。
该药物组合物含有本发明的肽或其药学上可接受的盐作为活性成分。
此外,上述药物组合物还包含药学上可接受的添加剂,因此上述药物组合物可以由本发明的肽或其药学上可接受的盐和上述添加剂组成。
本发明的肽可以通过通常用于肽化学领域的方法来制备。例如,可以通过Schroder和Lubke“The Peptides”Vol.1,Academic Press,New York(1965)所公开的方法,或通过例如溶液合成或固相合成的方法。
形成肽键的方法的实例可以包括酰基叠氮法、酰基卤化法、酰基咪唑法、碳化二亚胺法、膦法、酸酐法、混合酸酐法、氧化还原法和使用伍德沃德氏试剂K。
在缩合反应之前,可以保护不参与反应的羧基、氨基等,并且参与缩合反应的羧基可以通过本领域已知的方法活化。
用于保护羧基的官能团的实例可以包括形成酯的基团,例如甲基、叔丁基、芳基、五氟苯基、苄基、对甲氧基苄基和甲氧基乙氧基甲基。
用于保护氨基的官能团的实例可以包括三苯甲基羰基、芳氧基羰基、环己氧基羰基,三氯乙氧基羰基、苄氧基羰基、叔丁氧基羰基和/或9-芴基甲氧基羰基。
羧基的活性形式的实例可以包括:混合酸酐、叠氮化物、酰氯和活性酯[与醇(例如五氯苯酚、2,4-二硝基苯酚、氰甲基醇、对硝基苯酚、N-羟基-5-降冰片烯-2,3-二羧基酰亚胺、N-羟基琥珀酰亚胺、N-羟基邻苯二酰胺、或1-羟基苯并***)的酯]。
可用于形成肽键的缩合反应中的溶剂可以包括:苯、甲苯、己烷、丙酮、硝基甲烷、环己烷、***、氯仿、二氯甲烷、乙酸乙酯、N、N-二甲基甲酰胺、二甲亚砜、吡啶、二恶烷、四氢呋喃、水、甲醇和乙醇,它们可以单独使用或组合使用。
反应温度约为-70~100℃,优选-30~30℃。
从肽中除去保护基的脱保护反应可以根据保护基的种类使用能够除去保护基而不影响肽键的酸化合物、碱化合物或过渡金属进行。
脱保护反应可以通过使用例如氯化氢、溴化氢、氟化氢、乙酸、甲磺酸、三氟甲磺酸、三氟乙酸、三甲基氯硅烷、或它们的混合物的酸处理进行。
当通过酸处理进行脱保护反应时,可以通过加入例如茴香醚、苯酚或苯甲硫醚的助剂促进脱保护反应。
可选地,脱保护反应可以通过使用例如氨、二乙胺、肼、吗啉、N-甲基吡咯烷、哌啶、碳酸钠、或它们的混合物的碱处理进行。
可选地,脱保护反应可以通过使用例如锌、汞、钯/氢等的过渡金属处理进行。
反应完成后,可以使用典型的纯化方法如提取、层分离、固体沉淀、重结晶或柱层析等纯化肽。
此外,本发明的肽可以使用典型的处理来转化为其变体或其药学上可接受的盐。
本发明的肽可以使用自动肽合成仪合成,或者可以通过基因工程生产。例如,通过基因工程生产编码包含融合伴侣和本发明的肽的融合蛋白的融合基因,然后用于转化宿主微生物,由此使融合蛋白在宿主微生物中表达,然后使用蛋白水解酶或化合物将本发明的肽从融合蛋白中裂解或分离,从而产生期望的肽。
上述肽或其药学上可接受的盐以200-500mg/天,优选267-400mg/天的量肠胃外给药。上述给药的肽或其药学上可接受的盐可以用于成年人(约60kg)。口服给药时,量相当于肠胃外给药量的2-5倍。本发明的肽可以主要通过肠胃外途径给药,例如局部注射、静脉内或皮下注射、脑内或脊柱内给药、或者鼻内或直肠内给药。某些情况下,也可以口服给药。
本发明的肽或组合物可以与药学上可接受的添加剂一起配制成注射剂、栓剂、粉剂、滴鼻剂、颗粒剂或片剂的形式。
药学上可接受的添加剂可以根据本领域技术人员公知的多种因素来应用,包括例如特定的生物活性物质,其浓度、稳定性和预期的生物利用度;待治疗的病症和疾病或与之相关的状况;待治疗的个体,其年龄、身材和一般健康状况;以及组合物给药途径,例如鼻腔、口腔、眼睛、局部、皮肤和肌肉途径,但是本发明不限于此。除了口服给药途径之外,用于给药生物活性物质的药学上可接受的添加剂还可以包括D5W(5%葡萄糖水溶液)、含量为5体积%以内的右旋糖(dextrose)和生理盐的水溶液。对于局部病灶内注射,可以使用任何可注射水凝胶(hydrogel)来增强治疗效果并延长持续时间。药学上可接受的添加剂可以含有用于改善活性组分稳定性的附加组分,例如防腐剂和抗氧化剂等。本发明的肽或组合物可以通过在相关领域中的适当方法来生产,例如优选通过Remington's PharmaceuticalScience,Mack Publishing Company,Easton PA(最新版)中公开的方法配制以适合于每种疾病或组分。
本发明的肽可以保存在生理盐水中,也可以在添加甘露醇或山梨糖醇后在安瓿中冷冻干燥,也可以在生理盐水中溶解后给药。
此外,本发明提供了一种治疗或预防癌症的方法,该方法包括将本发明的肽或其药学上可接受的盐给药至需要给药的包括人在内的哺乳动物。此外,本发明提供了本发明的肽或其药学上可接受的盐在制造抗癌药物中的应用,并且优选用于制造用于治疗或预防癌症的药物。上述癌症的治疗或预防可以通过抑制选自癌细胞的侵袭和转移中的至少一种来实现。上述给药的肽或其药学上可接受的盐可以是有效量的肽或其药学上可接受的盐。
除非另外提及,根据本发明的肽或其药学上可接受的盐、应用、组合物和方法描述的事项,只要它们不相互矛盾,在相同的范围内彼此适用。
根据本发明,可以有效治疗或预防癌症。
附图说明
图1是表示本发明一个实施方式的对癌细胞侵袭效果的图;
图2是表示本发明一个实施方式的对癌细胞转移效果的图;
图3和4是表示本发明的一个实施方式的抗癌效果的图。
具体实施方式
通过以下实施例和制备例可以更好地理解本发明,这些实施例和制备例仅仅是为了举例说明而不能解释为限制本发明。
术语“抗癌”是指治疗或预防癌症的能力,特别是可以通过抑制选自癌细胞的侵袭和转移中的至少一种来显示抗癌效果。
以下实施例中使用的试剂是可商购的最好的产品,除非另有说明,购自Sigma-Aldrich。
<实施例1>肽的制备
由SEQ ID NO:1的氨基酸序列组成的肽(QLHLD:SEQ ID NO:1)由韩国AnyGen Co.,Ltd.制备。具体地,通过使用Fmoc(9-芴基甲氧基羰基)的化学性质的固相法合成。更具体地,将肽的C-末端与0.55mmol/g固体树脂(Wang resin;Sigma-Aldrich)偶联。用O-苯并***-N,N,N',N'-四甲基-脲-六氟磷酸盐(HBTU)进行Fmoc-Phe-OH氨基酸的偶联。用叔丁基和叔丁氧羰基保护氨基酸侧链。在室温下使用含有比例为95:5(v/v)的三氟乙酸和水的混合溶液进行3小时的脱保护和树脂分离。用二***反复洗涤粗肽,真空干燥,然后使用岛津Shimadzu 5μm Shimpak ODS C18柱(20×250mm)通过反相高效液相色谱(RP-HPLC)纯化粗肽。通过使用Shimpak 5μm ODS C18柱(4.6×250mm)的分析型RP-HPLC鉴定纯化的肽。使用基质辅助激光解吸电离(MALDI)-质谱仪(Axima CFR,Kratos Analytical,Manchester,UK)测量合成的肽的分子量。
<实施例2>对癌细胞侵袭的抑制效果评价
实验评价实施例1的肽对癌细胞的侵袭是否抑制。具体地,为了评价实施例1的肽抑制癌细胞侵袭的效果,进行了Transwell侵袭实验。用培养基{RPMI 1640培养基(WelgeneInc.,韩国)}将生长因子减少基质胶(Growth factor reduced Matrigel,BDBiosciences,Franklin Lakes,NJ,USA)以1:1稀释,并将其70μl加入到Transwell小室的上室(Corning cat#3422,Tewksbury MA,USA),然后在37℃的CO2培养箱中进行1小时的包被工序。向下室中加入500μl含有10%胎牛血清(FBS,Cellgro cat#35-015-CV,USA)的培养基{RPMI 1640培养基(Welgene Inc.,韩国)},然后向实验组加入10ng/ml的TGF-beta1(PromoKine,德国)。将包被的上室安装到下室,并将100μl含有0.5%FBS和20000个SNU-790甲状腺癌细胞(韩国细胞系库)的RPMI 1640培养基添加到上室。用同样的方式制备阴性对照组和两个实验组。用实施例1的肽以40μM和100μM的量处理对应的实验组,阴性对照组不用实施例1的肽处理。此外,除了不添加TGF-beta1(转化生长因子β1)外,以与阴性对照组相同的方式制备对照组。
实验组、对照组和阴性对照组在37℃的CO2培养箱中培养2天。培养完成后,使用棉签将在上室内剩余的细胞完全除去。用DPBS(Dulbeco's Phosphate-Buffered Saline)洗涤附着于上室外表面的细胞5分钟,在-20℃在100%甲醇中固定5分钟,然后用Mayer's苏木素溶液(Sigma-Aldrich)染色15分钟,再用自来水清洗5分钟,在100%乙醇中固定5分钟,然后用曙红Y溶液染色15分钟。最后用100%乙醇进行清洗,将附着有细胞的膜用刮刀切断,放置在载玻片上,用显微镜观察。对随机选择的四个区域进行拍照,并对这些区域中的细胞数量进行计数、取平均值和绘图。图1是显示上述结果的图,以各组为x轴、侵袭细胞的数量为y轴绘制。如图1所示,由TGF-beta1增加的癌细胞的侵袭被实施例1的肽浓度依赖性地抑制。
因此,本发明的肽在抑制癌细胞侵袭方面是有效的,由此表现出抗癌效果。
<实施例3>癌细胞体内转移抑制效果的评价
通过实验评价癌细胞的转移是否受到实施例1的肽的抑制。具体地,为了评价实施例1的肽对癌细胞的转移的抑制效果,使用4T1小鼠乳腺癌细胞(ATCC CRL-2539,USA)的肺转移模型进行实验。将实施例1的肽注射到雌性BALB/c小鼠(SPF,SLC/日本)尾部的尾静脉中。实验组根据注射浓度分为三组;低浓度{40μg/头}、中浓度{80μg/头}和高浓度{120μg/头}。阴性对照组进行与实验组相同的处理,不同的是不给药实施例1的肽。在第一次给药后的第二天,将4T1细胞(1.5×104个细胞/头)注射到小鼠尾部尾静脉中。1小时后,二次给药实施例1的肽。从第二次给药日到最终给药日,一周三次(星期一、星期三和星期五)进行三周肽的给药。每周测量两次小鼠的体重,在注射癌细胞后第21天进行尸体解剖。切除肺组织,用Bouin's溶液染色并固定,然后计数转移性肿瘤结节的数量。另外,除了不注射实施例1的肽和4T1细胞以外,将与实验组相同的方式处理的组(正常组)作为对照组。结果如图2所示。图2以各组为x轴、肿瘤结节的数量为y轴绘制。由此,n表示各组中个体的数量,P表示显著性概率。如图2所示,在以中浓度和高浓度给药实施例1的肽的实验组中,肿瘤结节的数量显著减少(P<0.001)。特别是在中浓度给药的实验组中,癌转移的抑制效果最高。
因此,本发明的肽在抑制癌细胞的转移方面是有效的,从而表现出抗癌效果。
<实施例4>抗癌效果的评价I
通过实验评价实施例1的肽的抗癌效果。具体地,为了评价实施例1的肽对患有癌症的存活个体的效果,使用与实施例3相同的方法制作的动物模型来测定存活率。
除了尸体解剖和随后的处理以外,按照与实施例3中的相同方式制备阴性对照组和实验组。为了测量存活率,观察和记录每组的存活率。结果如图3所示。在表示存活率的图3中,x轴表示自给药结束后的天数,y轴表示存活率(%)。另外,n表示各组中个体的数量。如图3所示,在以中浓度和高浓度给药实施例1的肽的实验组中,甚至在阴性对照组死亡后仍有一些个体存活。特别是在中浓度给药的实验组中,存活率最高。
因此,可以发现本发明的肽显示抗癌效果。
<实施例5>抗癌效果的评价II
通过实验评价实施例1的肽的抗癌效果。具体地,为了评价实施例1的肽对患有癌症的存活个体的效果,使用B16-BL6小鼠黑素瘤细胞的动物模型测定存活率(韩国细胞系库,韩国)。
将B16-BL6细胞{1x105细胞/头}皮下注射入7周龄雄性C57BL/6J小鼠(OrientbioInc.,韩国)。一周后,腹腔内给药实施例1的肽。实验组根据注射浓度分为三组;低浓度{40μg/头}、中浓度{80μg/头}和高浓度{120μg/头}。阴性对照组进行与实验组相同的处理,不同的是不给药实施例1的肽。从第一次给药日开始,每周重复给药两次,持续两周,然后每周一次,再给药四周,总共给药八次。为了测量存活率,观察和记录每组的存活率。结果如图4所示。图4中示出了存活率,x轴表示自注射癌细胞以来的天数,y轴表示存活率(%)。此外,n表示每组中个体的数量,P表示显著性概率。如图4所示,给药了实施例1的肽的实验组中,甚至在阴性对照组死亡后仍有一些个体存活。特别是在中浓度给药的实验组中,存活率最高。
因此,可以发现本发明的肽显示出抗癌效果。
<制备例1>
制备注射剂型
将按照实施例1相同的方法制备的500mg肽溶解在生理盐水中得到10ml溶液。将该溶液装入注射用安瓿中,得到注射用剂型。
工业应用
本发明能够有效治疗或预防癌症,因此可在工业上适用。
序列表
<110> 因首生物科学有限公司
<120> 新型肽及其应用
<130> P48969KRO
<150> KR 10-2015-0104332
<151> 2015-07-23
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 1
Gln Leu His Leu Asp
1 5
Claims (5)
1.由SEQ ID NO:1的氨基酸序列组成的肽或其药学上可接受的盐。
2.一种用于治疗或预防癌症的药物组合物,其中,该药物组合物包含权利要求1所述的肽或其药学上可接受的盐。
3.根据权利要求2所述的药物组合物,其中,所述癌症的治疗或预防通过抑制选自癌细胞的侵袭和转移中的至少一种来实现。
4.权利要求1所述的肽或其药学上可接受的盐在制造用于治疗或预防癌症的药物中的应用,其中,所述癌症选自甲状腺癌、黑素瘤和乳腺癌组成的组。
5.根据权利要求4所述的应用,其中,所述癌症的治疗或预防通过抑制选自癌细胞的侵袭和转移中的至少一种来实现。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0397635A1 (en) * | 1989-05-10 | 1990-11-14 | Monsanto Company | Peptide with anti-metastasis activity |
CN101151273A (zh) * | 2005-02-01 | 2008-03-26 | 阿特努奥恩公司 | Ac-PHSCN-NH2的酸加成盐 |
CN102892776A (zh) * | 2010-06-30 | 2013-01-23 | 因首太克株式会社 | 新型肽及其用途 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5595756A (en) * | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
US6451969B1 (en) | 1999-01-15 | 2002-09-17 | The Burnham Institute | Methods for inhibiting tumor metastasis, and peptides useful therfor |
ITRM20030386A1 (it) * | 2003-08-05 | 2005-02-06 | Istituto Naz Per Le Malattie Infettive Lazz | Metodo e test diagnostici basati sull'analisi citofluorimetrica dei linfociti t antigene-specifici. |
KR100794499B1 (ko) | 2006-05-16 | 2008-01-16 | 주식회사 프로메디텍 | 개구린 5로부터 합성 및 제조된 항생 및 항암 신규펩타이드 유도체 |
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WO2012060480A1 (ko) * | 2010-11-02 | 2012-05-10 | 인하대학교 산학협력단 | 암전이를 억제하는 항원 펩타이드, 이를 포함하는 암전이 백신, 암전이 억제 및 치료용 조성물 그리고 암전이 관련 표적물질 및 암전이 억제물질의 스크린 방법 |
CA2822775A1 (en) * | 2011-01-04 | 2012-07-12 | Charite Universitatsmedizin Berlin | Modulators of il-12 and/or il-23 for the prevention or treatment of alzheimer's disease |
CA2862485C (en) * | 2012-01-24 | 2021-05-11 | Inter-K Pty Limited | Peptide agents for cancer therapy |
JP6078844B2 (ja) * | 2012-09-26 | 2017-02-15 | 公立大学法人大阪市立大学 | 癌免疫療法のためのペプチド及びその利用 |
KR102067613B1 (ko) * | 2013-03-28 | 2020-01-20 | 삼성전자주식회사 | 항 c-Met 항체 및 항 her2 항체를 포함하는 병용 투여용 조성물 |
KR101467676B1 (ko) * | 2013-04-12 | 2014-12-04 | 울산대학교 산학협력단 | 암 표적용 펩타이드 및 이의 의학적 용도 |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0397635A1 (en) * | 1989-05-10 | 1990-11-14 | Monsanto Company | Peptide with anti-metastasis activity |
CN101151273A (zh) * | 2005-02-01 | 2008-03-26 | 阿特努奥恩公司 | Ac-PHSCN-NH2的酸加成盐 |
CN102892776A (zh) * | 2010-06-30 | 2013-01-23 | 因首太克株式会社 | 新型肽及其用途 |
Non-Patent Citations (2)
Title |
---|
Amino Acid Properties and Consequences of Substitutions;Matthew J Betts等;《Bioinformatics for Geneticists》;20031231;第296-299和第306-307页 * |
Filamentous tropical marine cyanobacteria: a rich source of natural products for anticancer drug discovery;Lik Tong Tan等;《J Appl Phycol》;20100223;第22卷;全文 * |
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